Non-castrate Metastatic Prostate Cancer: Have theTreatment Options Changed?

Phillip L. Palmbos and Maha Hussain

Over the past 7 decades androgen-deprivation therapy (ADT) has been the cornerstone of

treatment for metasta

achieve this goal have

but also gonadotropinandrogen receptor (A

castrate-resistant prost

CRPC have emerged. Tthis review, we outline

for NCPC, and discuss

Semin Oncol 40:337-3

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Seminars

tic non-castrate prostate cancer (NCPC); however, the mechanisms to

evolved over time to include not only bilateral orchiectomy and estrogens,

-releasing hormone (GnRH) agonists, antagonists, and the inclusion ofR) blockade. Despite treatment with ADT, most men will progress to

ate cancer (CRPC). Over the last decade many new treatment options for

hese new treatments also could have a meaningful role earlier in NCPC. Inthe biologic drivers of NCPC, review current standard therapy available

the evolving role of new therapeutics in metastatic disease.

46 & 2013 Elsevier Inc. All rights reserved.

Despite many decades of research, metastatic

prostate cancer remains a lethal disease,claiming 28,170 lives per year in the United

States and representing the second most common

malignancy-related death in men.1 Prostate cancer isan androgen-dependent tumor and the vast majority

of new metastatic prostate cancers (non-castrate

prostate cancer [NCPC]), are initially responsive toandrogen-deprivation therapy (ADT). However, ADT

is not curative and most patients will ultimately

progress to castration-resistant prostate cancer(CRPC).2 The last decade has seen the approval of

multiple new treatments for CRPC, but these new

therapeutic modalities are not curative and their rolein NCPC remains to be defined.3 To advance pros-

tate cancer care, we must now move these novel

therapies to earlier stages of disease, determine theoptimal timing and use of existing therapies, and

develop biomarkers that identify patients likely to

benefit from new targeted therapies. In this reviewwe will outline the biologic drivers of NCPC, review

current standard therapy available for NCPC, and

- see front matterevier Inc. All rights reserved.i.org/10.1053/j.seminoncol.2013.04.007

f interest: Dr Hussain receives research support from Abbot,y, EMD Sorrano, Astellas, Takeda and Millenium. She is afor: Genmab, Exelexis.

t of Internal Medicine, Division of Hematology/Oncology,ty of Michigan, Ann Arbor, MI.

orrespondence to Maha Hussain, MD, Department ofMedicine, Division of Hematology/Oncology, Universitygan, 1500 E Medical Center Dr, 7314 CCGC, Ann Arbor,9-5946. E-mail: mahahuss@med.umich.edu

in Oncology, Vol 40, No 3, June 2013, pp 337-346

discuss the evolving role of new therapeutics in

metastatic disease.

ANDROGENS AND THE PROSTATE

The prostate gland requires androgens for forma-

tion and patients who lack the enzymes responsiblefor androgen biosynthesis do not develop a prostate.4

Prostate adenocarcinoma also requires androgen-

induced activation of androgen receptors (ARs) forgrowth and survival; disruption of this pathway stops

prostate cancer proliferation and induces apoptosis.2

Hormonal therapy for metastatic NCPC targets thegonadal and adrenal pathways responsible for andro-

gen production, starving prostate cancers of this

essential growth stimulant (Figure 1).Gonadal androgen production by the testis is

governed by the hypothalamus, which produces

rhythmic pulses of gonadotropin-releasing hormone(GnRH), which in turn stimulates the pituitary to

release luteinizing hormone (LH) and follicle-

stimulating hormone (FSH). LH stimulates Leydigcells in the testis to convert precursor steroid

molecules into testosterone and dehydroepiandro-

sterone (DHEA) (Figure 1). Although testosterone isthe predominant male hormone, dihydrotestoster-

one (DHT) is the more potent AR agonist; it is

produced by conversion from testosterone withinperipheral tissues and the prostate itself.2 Because

most of the testosterone is produced in the testis,

bilateral orchiectomy rapidly reduces testosteroneto o50 ng/mL.2 Furthermore, since most intrapro-

static DHT is produced by conversion from testos-

terone, loss of circulating testosterone reduces DHT

337

Hypothalamus

Pituitary

Tes�sAdrenal

Prostate Cancer

TestosteroneDHEAS

DHT

LHACTH

GnRHCRH Leuprolide, Goserelin, DES,

DegarelixGlucocor�coids

Ketoconazole, Abiraterone CYP17A1CYP17A1

Biclutamide, Nilutamide, Flutamide,

EnzalutamideARN-509

Androgen Receptor

Figure 1. Androgen regulation and prostate cancer.

P.L. Palmbos and M. Hussain338

levels by 70%–80%, thereby reducing the prolifer-

ative stimulus within the tumor tissue.4

Adrenal androgen production is also regulatedby the hypothalamic-pituitary axis. Secretion of cor-

ticotropin-releasing hormone (CRH) by the hypothal-

amus stimulates the pituitary to release adrenocorti-cotropic hormone (ACTH), which in turn stimulates

the adrenal cortex to produce the androgen, DHEA

(Figure 1). Similar to testosterone, DHEA can beconverted to DHT in peripheral tissues and the

prostate.4 Adrenal production of androgens likely

accounts for the observation that prostate tumorsretain DHT levels 20%–30% of normal even after

medical or surgical castration.4 This alternative path-

way of androgen production can be targeted bytreatment with exogenous corticosteroids, which

block production of ACTH and subsequent adrenal

production of androgens or by drugs that inhibit theadrenal enzymes responsible for androgen production

(Figure 1). Indeed, corticosteroids do have intrinsic

activity in CRPC and are frequently used after diseaseprogression following medical or surgical castration

or in conjunction with cytotoxic chemotherapy,

although they have not been tested in randomizedtrials.5 Most current treatments for metastatic NCPC

target various aspects of these two pathways.

TREATMENT OF METASTATIC NCPC:HISTORICAL PERSPECTIVE

Orchiectomy and Estrogens

The first treatment for men with advanced prostateadenocarcinoma was described more than 70 years

ago by Huggins and Hodges who found that men

treated with bilateral orchiectomy or with the estrogen,

diethylstilbestrol (DES) displayed clinical improve-ments.6 Both orchiectomy and DES resulted in suppres-

sion of gonadal androgen production; orchiectomy,

by removal of the androgen-secreting tissue, and DES,by provoking negative feedback on the GnRH/LH

regulatory pathway (Figure 1). This Nobel Prize win-

ning observation established hormonal therapy as theprimary treatment for metastatic NCPC and is founda-

tional to all current therapy for prostate cancer. In the

1960s, a large clinical trial conducted by the Veteran'sAdministration Cooperative Urological Research Group

(VACURG) randomized patients with advanced or

metastatic prostate cancer to either orchiectomy, DES,or both to determine which was most effective.7

Interestingly, DES did not confer a survival advantage

when compared to orchiectomy, primarily due toincreased risk of cardiovascular events. These toxicities

were in part due to the high dose of estrogens, which is

now a recognized risk factor for cardiovascular diseaseand thrombosis.8

GnRH Agonist/Antagonists

In the early 1980s synthetic peptide analogues of

GnRH were developed that targeted the pituitaryregulation of androgen production and allowed

medical castration. The most commonly used agents,

leuprolide or goserelin, are synthetic GnRH agoniststhat replace the normal pulsatile secretion of GnRH

with a continual agonism resulting in an initial pulse

of LH and androgen production, followed by sup-pression of both LH and testosterone to below 50

Non-castrate metastatic prostate cancer 339

ng/dL, a level of suppression similar to orchiectomy

(Figure 1).2 Randomized trials comparing GnRHagonists to DES in patients with metastatic prostate

cancer demonstrated that they were equally effica-

cious in reducing serum testosterone levels, hadsimilar overall survival and TTP and avoided many

of the limiting cardiovascular and thrombotic toxic-

ities associated with DES.9 Patient preference hasmade medical castration with GnRH agonists the

standard of care for newly diagnosed metastatic

prostate cancer.More recently, GnRH antagonists have been devel-

oped. Degarelix, is a GnRH antagonist that directly

blocks GnRH stimulation of the pituitary.10 A random-ized phase III trial of degarelix versus leuprolide

demonstrated that degarelix treatment produces

more rapid reduction in testosterone levels (castratelevels by day 3 of treatment), whereas patients treated

with leuprolide had a 65% increase in testosterone on

day 3 and required 28 days to achieve castratelevels.11 Another putative advantage of degarelix is

the absence of LH micro-surges associated with GnRH

agonist administration even after castrate levels oftestosterone are achieved. Whether these micro-

surges have an impact on patient outcomes remains

unclear. Further evaluation of the patients treatedwith degarelix has suggested that degarelix may

reduce the risk of prostate-specific antigen (PSA)

relapse in patients with more extensive disease butdid not alter survival.12

AR

+

AR

Prolifera�on

Transcrip�on

Survival

Apoptosis

BCL2 Clusterin

DNA Repair

Androgens IGF-1R c-MET

PI3K

AKT

mTOR

PTENRAS

RAF

MAPK

SRC

DNA

Nucleus

Cytoplasm

Amplifica�on, Muta�on

Figure 2. Signaling pathways governing growth andsurvival in prostate cancer.

Androgen Receptor Blockade

The emergence of castration resistance in men

treated with gonadal suppression is now understoodto depend in part on stimulation by androgens

produced by the adrenal glands. It was therefore

hypothesized that inhibition of the AR itself mightimprove outcomes in patients with metastatic NCPC

by blocking AR signaling mediated by adrenal andro-

gens. Since the late 1980s multiple trials of com-bined androgen blockade using primary gonadal

suppression, with and without concomitant AR

blockers, cyproterone acetate, flutamide, nilutamide,and biclutamide, were conducted to test this hypoth-

esis.13 Although some of these trials demonstrated a

survival or progression-free survival benefit, oppo-nents of this approach note that not all trials showed

significant benefits and that their cost and potential

for side effects limit their overall clinical utility. Ameta-analysis of 21 randomized clinical trials assess-

ing GnRH agonists alone or in combination with AR

blockade concluded that while there was no benefitto combined androgen blockade at 2 years when

compared to monotherapy, there was a modest and

statistically significant survival advantage to com-bined androgen blockade at 5 years.14 Therefore,

because of this survival advantage and minimal

added toxicity, combined androgen blockade hasbecome one of the standard treatment considera-

tions for metastatic disease.

BIOLOGY AND PREVENTION OF CASTRATE-RESISTANT PROSTATE CANCER

Progression from NCPC to CRPC requires evolu-tion from an androgen-dependent state to an

androgen-independent state. The mechanisms that

drive this progression include reactivation of ARsignaling or upregulation of other cellular pathways

controlling growth (Figure 2).15 Reactivation of AR

signaling in prostate cancer cells may be multifacto-rial but can involve genetic amplification or muta-

tional activation of the AR receptor, increased

intratumoral androgen production and upregulationof AR coactivators, all of which increases transcrip-

tional activation and proliferation (Figure 2).16

It has been suggested that androgen-independentcancer cells are present early in disease and

androgen-independent growth is driven by clonal

selection of these cells.17 If these androgen-independent clones could be targeted while the bulk

of the tumor is sensitive to androgen loss, then

eventual progression could be delayed or prevented.Two approaches to date to delay or prevent the

development of CRPC have been the subject of large

clinical trials. The first approach is based on thehypothesis that CRPC arises due to selective

pressure-induced ADT and that by limiting exposure

to selective pressure CRPC can be delayed oravoided. The second approach attempts to eliminate

resistant clones present early in disease using cyto-

toxic chemotherapy in combination with ADT.

Reducing Selective Pressure

Continuous androgen deprivation (CAD) maydrive Darwinian selection of androgen-insensitive

P.L. Palmbos and M. Hussain340

clones, leading ultimately to CRPC. Therefore, inter-

mittent androgen deprivation (IAD), which removescontinuous selective pressure could delay develop-

ment of CRPC in addition to reducing the side effects

related to ADT. This theory was supported bypreclinical mouse models in which androgen sup-

pression drove formation of androgen-independent

tumors.18 In addition, ADT has been associated withseveral toxicities, including osteoporosis, weight

gain, diabetes, cholesterol, and coronary artery dis-

ease, which potentially could be reduced by IAD.19

Prior to this year, four randomized trials had

addressed this question, with three supporting equiv-

alent survival and less adverse events in most patientsreceiving IAD when compared to continuous therapy

and one showing worse survival in a subset of

patients with higher risk disease (high pretreatmentPSA, more extensive/bulky disease).20–23 Although

intriguing, each of these trials was small with

heterogeneous populations and not adequately pow-ered to determine comparability/non-inferiority. The

definitive prospective randomized controlled study

regarding this question, Southwest Oncology Group(SWOG) 9346 (INT-0162) was recently reported.24

In this study, 1,535 patients with metastatic NCPC

who achieved PSA o4 following ADT were ran-domly assigned to either intermittent or continuous

ADT and survival, adverse events, and quality of life

were assessed. Interestingly, although this trial con-firmed some quality of life improvements in patients

in the IAD arm, it did not meet its primary endpoint,

which was IAD non-inferiority as compared to CAD.These findings suggest that contrary to preclinical

modeling and theory, patients receiving IAD may

have worse overall survival. In this context, it wouldseem that IAD is not a routine therapy and patients

wishing to undergo IAD must be carefully counseled.

Targeting “De Novo” Androgen-Dependentand -Independent Disease

A second strategy to delay or prevent CRPC is to

eliminate androgen-insensitive clones using cyto-

toxic therapy given concurrently with ADT inpatients with newly metastatic NCPC. Historically,

the addition of alkylating agents and anthracyclines

to ADT demonstrated improved response rates andpalliation but no survival advantage.25,26 In 2004,

two phase III studies demonstrated a survival benefit

in CRPC patients treated with docetaxel.27,28 Sincedocetaxel conferred a survival advantage in CRPC, it

was postulated that docetaxel might confer a sur-

vival advantage when combined with ADT in meta-static NCPC. This question is currently being

addressed in Eastern Cooperative Oncology Group

(ECOG) E3805 (CHAARTED), which randomizespatients with newly diagnosed metastatic prostate

cancer to either docetaxel plus prednisone with

ADT or ADT alone. Whether docetaxel offers asurvival advantage to patients who are starting ADT

or instead the toxicity of therapy outweighs

improved response will be determined.29

NEXT-GENERATION HORMONAL AGENTS

The realization that CRPC relies on reactivation of

AR signaling via AR amplification, mutation, and

extragonadal production of androgens made morepotent suppression of AR signaling a prime thera-

peutic target in patients with CRPC.30 Two success-

ful strategies have been developed to target thisresidual androgenic signaling in metastatic CRPC:

inhibition of the extragonadal synthetic pathways,

and more potent blockade of the AR.CYP17A, a 17α-hydroxylase/17,20-lyase, is present

in both testicular tissue and adrenal cortex and is

responsible for the conversion of pregnenolone intoDHEA and testosterone (Figure 1).4 Historically,

ketoconazole was used to block this enzymatic

pathway and represents a second-line hormonaltherapy for metastatic prostate cancer. Abiraterone

acetate is a newer CYP17A inhibitor that irreversibly

blocks CYP17A production of DHEA from steroidprecursors (Figure 1).31 Interestingly, inhibition of

CYP17A also blocks production of cortisol, resulting

in increased ACTH and overproduction of othermineralocorticoid precursors. For this reason, all

patients must also receive corticosteroids to sup-

press ACTH production and prevent symptoms ofmineralocorticoid excess.31 Importantly, when

administered with corticosteroids, abiraterone

extends survival in patients with CRPC who havepreviously received docetaxel (14.8 months v 10.9

months, P o.0001).32 Abiraterone now has been

approved for CRPC after docetaxel and the data forits use in early CRPC prior to chemotherapy also has

been reported.33 Although trials in metastatic NCPC

are proposed or ongoing, there is reason to assumethat such agents will have even a better anti-tumor

effect in NCPC.

Orteronel (TAK-700) is another 17α-hydroxylase/17,20-lyase inhibitor that is more selective for the

lyase function of CYP17A.34 This selectivity has the

advantage of reduced activation of the mineralocor-ticoid pathway and thus may have the benefit of not

requiring concomitant corticosteroids.35 Currently,

there are two large phase III clinical trials evaluatingthe efficacy of this compound in metastatic CRPC

before and after chemotherapy compared to placebo

(NCT01193257 and NCT01193244).Enzalutamide is a more potent AR blocker that

binds to AR with higher affinity than biclutamide and

prevents the AR from translocation to the nucleus.34

Enzalutamide now also has been reported to extend

Table 1. Prostate Cancer Pathways and Targets

Pathway Target Agent

Androgen signaling CYP17, androgen receptor Abiraterone, enzalutamide, ARN-509, TAK-700,TOK-001

Angiogenesis VEGF, VEGFR, PDGFR Olaratumab, tasquinomod, ramucirumabApoptosis BCL-2, clusterin AT-101, custirsenDNA repair PARP VeliparibBone microenvironment Integrins, RANK ligand EMD 525797, denosumabImmune system CTLA-4, tumor antigen Ipilimumab, sipuleucel-TReceptor tyrosine kinases IGF-1R, c-MET, SRC Cixutumumab, cabozantinib, casatinib

Abbreviations: VEGF/R- vascular endothelial growth factor/receptor, PDGF- platelet derived growth factor receptor, BCL-2- B celllymphoma 2, PARP- poly ADP ribose polymerase, RANK- receptor activator of nuclear factor kappa B, CTLA-4- cytotoxic Tlypmphocyte antigen 4, Insulin like growth factor 1R.

Non-castrate metastatic prostate cancer 341

the survival of patients with CRPC in a phase III

randomized placebo-controlled trial (median overall

survival, 18.4 v 13.6 months, respectively; hazardratio [HR] 0.631; P o .0001).36 The activity of more

potent AR blockade in CRPC indicates that they are

very likely to also have a role in patients withhormone-sensitive cancers.

Although, abiraterone, TAK-700, and enzaluta-

mide all show promising clinical activity in CRPC,development is already underway on third-

generation more potent inhibitors of androgen sig-

naling. TOK-001, a combined CYP17/anti-androgen,targets both CYP17-mediated production of andro-

gens and has anti-AR activity.37 A phase I trial has

recently completed accrual and results are pending(ARMOR1, NCT00959959). In addition, ARN-509, an

anti-AR agent with higher affinity for AR than

biclutamide and higher anti-tumor efficacy thanenzalutamide in preclinical models, is now being

tested in a phase I/II trial in patients with CRPC

(NCT01171898).38

The efficacy of both CYP17A inhibitors and more

potent AR blockade, even after extensive prior treat-

ment, raises the important question of whether earlierand more potent androgen suppression/blockade with

abiraterone, enzalutamide, or TAK-700 and similar

next-generation agents could improve survival inpatients with metastatic NCPC when tumors remain

maximally dependent on androgens for survival.

Recently reported data from a phase II trial ofabiraterone in combination with ADT in high risk

prostate cancer prior to surgery demonstrated that

addition of abiraterone increased PSA responses anddecreased DHT and DHEA levels suggesting a poten-

tial role for abiraterone in newly diagnosed disease.

Studies to determine the efficacy of abiraterone inconjunction with GnRH agonists in neoadjuvant set-

tings and as sensitizing agents for radiation are

ongoing (NCT01088529, NCT01023061). Moreover,the STAMPEDE trial includes an arm in which patients

with advanced NCPC will receive abiraterone and

ADT (NCT00268476). A phase II single-arm trial

addressing the inclusion of enzalutamide in earlierhormone-sensitive disease is also underway

(NCT01302041). Similarly, a recently approved con-

cept by SWOG will evaluate gonadal suppression plusbicalutamide versus gonadal suppression plus TAK-

700, in metastatic NCPC. Hopefully these trials will

begin to define the role of more effective androgensuppression in earlier stage disease and offer the

promise of preventing progression to CRPC.

BEYOND ANDROGENS—NEW TARGETS ANDDRUGS

The relative “diminishing returns” (modest sur-

vival improvements and efficacy in subsets of

patients) from strategies targeting androgen signal-ing in the setting of CRPC highlights the importance

of not only moving these agents to NCPC where a

better impact maybe possible but also to focus onother cellular pathways that contribute to the devel-

opment of CRPC.32 Clearly a better understanding of

the biology of progression is needed; however, manypathways have been identified and drugs targeting

these pathways are currently being explored

(Figure 2 and Table 1). If tolerable and effective inhumans, these agents may represent new options for

patients with newly metastatic NCPC.

One such pathway is the insulin-like growthfactor-1 (IGF-1) signaling pathway. IGF-1 binds to

IGF-1R, a receptor tyrosine kinase involved in cellu-

lar survival and proliferation in multiple tumor types,including prostate cancer.39 IGF-1R subsequently

activates the PI3K/AKT, RAS/MAPK, and SRC kinase

pathways, which drive proliferation and survival(Figure 2). Elevated IGF-1 has been identified as a

possible risk for development of prostate cancer and

prostate tumors have increased expression of IGF-1R.39 Several methods to block the IGF-1 pathway

P.L. Palmbos and M. Hussain342

have been explored, including anti-sense oligonu-

cleotides and more recently the monoclonal anti-body, cixutumumab (IMC-A12). Because IGF-1

signaling participates with androgenic signaling to

promote tumor growth, combination with ADTpromotes tumor response in preclinical models of

NCPC.40 This hypothesis is currently being evaluated

in SWOG S0925, a randomized phase II trial of ADTwith or without cixutumumab in metastatic NCPC

with the primary endpoint of undetectable PSA.

Apoptosis is another important mechanismwhereby tumors avoid cell death after treatment. In

CRPC, upregulation of bcl-2 and clusterin blocks

apoptotic pathways and may provide a partialexplanation of resistance to cytotoxic chemotherapy

(Figure 2). AT-101 binds to bcl-2 and its related

family of anti-apoptotic proteins lowering cellularapoptotic threshold. A phase I clinical trial of AT-101

suggested disease-specific activity and a phase II trial

of AT-101 in combination with ADT in newlydiagnosed metastatic NCPC suggested a modest

increase in PSA response in patients with aggressive

disease.41,42 Likewise, the protein, clusterin,increases after androgen ablation and/or chemother-

apy, increasing cellular resistance to apoptosis.43

Custersin is an antisense oligonucleotide directedagainst clusterin, which lowers clusterin levels in

tumors. In a phase II trial of patients with CRPC

treated with docetaxel plus/minus custersin, therewas a suggestion of better survival for patients

receiving custersin (median survival, 23.8 v 16.9

months).44 These data led to a phase III trial ofcustersin in CRPC, which is currently enrolling

subjects. Because ADT induces upregulation of

anti-apoptotic proteins and induces apoptosis, itmay be reasonable to consider combining agents

targeting this pathway with ADT in metastatic NCPC

as well.Vascular endothelial growth factor (VEGFR) and

c-MET are receptor tyrosine kinases that govern

prostate cancer growth, angiogenesis, and boneremodeling. Although small trials testing agents that

target the VEGFR pathway (bevacizumab, sunitinib)

suggested possible anti-tumor activity in prostatecancer, confirmatory phase III trials have failed to

demonstrate survival benefits in patients with

CRPC.45–47 Other VEGF inhibitors are being eval-uated (Table 1). Interestingly, cabozantinib, a small-

molecule inhibitor of c-MET, VEGFR2, and multiple

tyrosine kinases, has shown promise in CRPC.A phase II trial of patients with metastatic CRPC

treated with cabozantinib demonstrated remarkable

reduction in metastatic bone disease and relief ofbone pain.48 c-MET expression increases with pros-

tate cancer progression and is associated with meta-

static disease, as well as angiogenesis (Figure 2).49,50

Interestingly, AR signaling also appears to repress

c-MET expression, and castration actually increases

c-MET expression.50 These findings imply that ADTdirectly participates in the emergence of castrate

resistance by upregulation of c-MET. Therefore, it is

rational to postulate that the combination of ADTwith c-MET multi-targeting agents like cabozantinib

or others might offer the potential of delaying the

development of CRPC.In patients with CRPC and bone metastasis,

inhibitors targeted at osteoclast activation have

proven to be an important adjunct to therapy.Specifically, bisphosphonate therapy with zolen-

dronic acid or the RANK ligand inhibitor, denosu-

mab, reduces skeletal-related events (SRE) in patientswith CRPC.51–53 These findings could suggest that

bone-protective agents might benefit patients with

metastatic NCPC. Despite this, a trial of thebisphosphonate, clodronate, did not show statisti-

cally significant improvements in survival or bone-

related events in patients with newly diagnosedmetastatic prostate cancer.54 A larger study, Cancer

and Leukemia Group B (CALGB) 90202, randomly

assigned 680 men with metastatic NCPC to eitherzolendronic acid or placebo and measured time to

first SRE or death. This study may help define

whether there is a role for bone-targeted agents inNCPC, but results are pending. Until then, the only

role for bone-stabilizing agents in metastatic NCPC is

for osteoporosis induced by ADT.Provoking the immune system to recognize and

exert an anti-tumor effect has been an important goal

for many years. Sipuleucel-T is an active cellularimmunotherapy consisting of host antigen-

presenting cells (APCs), which have been sensitized

to recognize prostate cancer by co-culture withprostatic acid phosphatase and granulocyte–macro-

phage colony-stimulating factor. This agent received

US Food and Drug Administration approval based ona survival advantage in a phase III trial.55–57 The

survival advantage in CRPC provokes interest in

using immunotherapy earlier in the course of pro-state cancer to prevent development of metastatic

disease or CRPC when disease burden is low. The

PROTECT trial is a phase III study randomizingpatients with biochemically recurrent prostate can-

cer after prostatectomy to either sipuleucel-T or

placebo with a primary endpoint of time to pro-gression and may begin to elucidate the optimal

timing of this controversial therapeutic in non-

castrate disease (NCT00779402).Ipilumimab is an anti-cytotoxic T-lymphocyte

antigen-4 (CTLA4) monoclonal antibody. Normally,

CTLA4 deactivates cytotoxic T lymphocytes, andipilumimab interferes with this process allowing

development of an anti-tumor cytotoxic response.

Early studies suggest that treatment of patients withprostate cancer can induce a cytotoxic immune

Non-castrate metastatic prostate cancer 343

response directed at tumor.58 A phase II trial in

patients with advanced prostate cancer demon-strated that addition of ipilumimab to ADT improved

PSA responses and resulted in significant disease

down-staging in a fraction of patients.59 Additionaltrials are ongoing to explore the role of ipilumimab

in both CRPC and NCPC (NCT01377389 and

NCT00170157).

STRATEGIES FOR SUCCESS: EVALUATINGNOVEL THERAPIES IN METASTATIC NCPC

The large number of new hormonal and targetedagents make it essential to develop rational strategies

to approach clinical evaluation in metastatic NCPC

patients. Many patients will do well on traditionalADT for years and therefore the risks, costs, and

benefits of potential treatments must be weighed

carefully. For these reasons, several factors must beconsidered when designing trials to test these novel

agents.

First, trials must be designed with the under-standing that many patients with NCPC have a

relatively long survival. The overall survival for

newly diagnosed metastatic prostate cancer patientshas improved markedly over the last 20 years. In a

recent comparison of SWOG phase III clinical trials

(S8494, S8894, S9346) conducted in newly meta-static NCPC patients sequentially between 1985 and

2009, patients in S9346 demonstrated improved

median survivals compared to the earlier trials (49months v 30 and 34 months in the earlier trials) and

a 22% lower risk of death in S9346 compared to

S8894 (hazard ratio, 0.78; 95% confidence interval,0.70–0.87; P o.001).60 Indeed, patients in the S9346

study who achieved a PSA o0.2 ng/mL at 6–7months after ADT had a median survival of 75months.61 These results illustrate that many patients

with newly metastatic NCPC can expect to live 5–10years following diagnosis. Because of this, trialsassessing new drugs and treatment strategies in

NCPC must be designed and powered to detect

survival advantages that may not be apparent formore than 5–10 years.

Second, future trials should target high-risk

patient populations or those who are most likely torespond to therapy. Metastatic NCPC is a diverse

disease and while some patients never progression

on ADT, others rapidly progress and die fromdisease. Unlike some other cancers, we currently

have very limited tools to determine good and poor

prognosis at the time of diagnosis of metastaticdisease.62 One such tool is PSA response to initial

ADT. In S9346 (INT-0162), patients who did not

achieve a PSA o4 ng/mL after 6–7 months had amedian survival of less than 2 years, whereas

patients with a PSA o0.2 ng/mL had a median

survival of over 75 months.61 Clearly, patients withpoor PSA response to initial ADT are a group that

could derive benefit from improved therapy and may

therefore represent a group for which intensificationof therapy is justified using novel agents such as

abiraterone or enzalutamide to potentially improve

outcomes.Third, the pathways that drive prostate cancer

progression and growth are complicated and often

redundant and it is unlikely that single targetedagents will be effective (Figure 2). As trials to

examine newer targeted therapies in NCPC con-

tinue, it is essential to develop the correlativescience to define which patient groups will benefit

from single or combined targeted therapies. The

advent of personalized medicine, including molec-ular categorization and tumor genome sequencing,

may allow us to further target treatments to sub-

groups. To develop meaningful treatments, we willneed to define the pathways that drive an individual

tumor and then target them accordingly.

Fourth, although overall survival remains the goldstandard for phase III trials, the relatively long overall

survival for patients with newly diagnosed metastatic

NCPC makes survival endpoints impractical forsmaller phase II trials, which are necessary for

evaluation of novel agents. Therefore, the develop-

ment of accurate and predictive surrogate markers ofsurvival is essential. Pending the development of

better predictive biomarkers it is possible that using

PSA decline rates as an intermediate biomarker toefficiently test new treatment strategies before

embarking on large phase III trials is a reasonable

approach.Finally, all treatments must be judged not only by

their ability to prolong life but also on their associ-

ated costs, both side effect profile and cost-effectiveness. In CRPC patients, where survival is

measured in months, a small survival benefit and

greater toxicity could be tolerated, whereas NCPCpatients, who may live a decade or longer, may not

wish to suffer similar toxicities for proportionally

smaller benefits.

BEYOND CASTRATION—EXPLORING THEEVOLVING LANDSCAPE OF PROSTATECANCER CARE

In truth, the principles of treatment for metastatic

NCPC have not changed yet, but we now have more

tools to deliver standard care. Over the last decadecreative approaches to cytotoxic therapy and

improved molecular targeting of androgen signaling

have resulted in many treatment options for patientswith CRPC who previously had a grim prognosis.

P.L. Palmbos and M. Hussain344

The challenge for the next decade will be to

determine the optimal sequencing and combinationsof these novel agents, potentially moving them ear-

lier in the disease course either as adjuvant therapies

or at presentation with metastatic NCPC. Although asubset of NCPC patients currently enjoys survival

estimates of 5–10 years, it is feasible that more

profound androgen suppression earlier in diseasewill specifically benefit patients with higher-risk

disease (poor PSA response) improving their dismal

prognosis. Based on our current understanding ofthe biologic drivers of prostate cancer progression, it

is reasonable to expect that deeper androgen depri-

vation in prostate cancer at an early stage when it ismost sensitive to androgen stimulus may produce

better and more durable disease responses, resulting

in prolonged survival and delayed progressionto CRPC.

In addition, we are starting to glimpse the path-

ways that drive prostate cancer to lose dependenceon androgen signaling. New drugs targeting these

pathways that drive survival and proliferation are

constantly being developed. The challenge of thesenew targeted drugs will be selecting and combining

agents in subsets of patients most likely to benefit

from them. To better define these categories, adeeper understanding of the biology of NCPC is

required. Perhaps next-generation sequencing and

molecular techniques will allow us to target path-ways instead of histology. While the role for these

novel hormonal and targeted agents remains to be

defined in clinical trials, it is likely that the biologicprocesses that they target are relevant in both NCPC

and CRPC, and therefore they may ultimately join a

growing armamentarium in the fight against prostatecancer.

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